Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease.

Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

[1]  E. Hol,et al.  Astrogliosis: An integral player in the pathogenesis of Alzheimer's disease , 2016, Progress in Neurobiology.

[2]  Hemant R. Jadhav,et al.  Reactive Astrogliosis: Role in Alzheimer's Disease. , 2015, CNS & neurological disorders drug targets.

[3]  N. Seeram,et al.  Anti-Inflammatory Effects of Novel Standardized Solid Lipid Curcumin Formulations. , 2014, Journal of medicinal food.

[4]  Michael T. Heneka,et al.  Innate immune activation in neurodegenerative disease , 2014, Nature Reviews Immunology.

[5]  A. Alizadeh,et al.  Nanotechnology-Applied Curcumin for Different Diseases Therapy , 2014, BioMed research international.

[6]  W. Tripanichkul,et al.  Ameliorating effects of curcumin on 6-OHDA-induced dopaminergic denervation, glial response, and SOD1 reduction in the striatum of hemiparkinsonian mice. , 2013, European review for medical and pharmacological sciences.

[7]  Yunliang Wang,et al.  Curcumin as a potential treatment for Alzheimer's disease: a study of the effects of curcumin on hippocampal expression of glial fibrillary acidic protein. , 2013, The American journal of Chinese medicine.

[8]  K. Chuang,et al.  Specific Inhibition of p25/Cdk5 Activity by the Cdk5 Inhibitory Peptide Reduces Neurodegeneration In Vivo , 2013, The Journal of Neuroscience.

[9]  H. Pant,et al.  A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  E. Teng,et al.  Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice* , 2012, The Journal of Biological Chemistry.

[11]  Young Hun Kim,et al.  Anti-inflammatory effects of aromatic-turmerone through blocking of NF-κB, JNK, and p38 MAPK signaling pathways in amyloid β-stimulated microglia. , 2012, International immunopharmacology.

[12]  P. Bickford,et al.  Optimized Turmeric Extract Reduces β-Amyloid and Phosphorylated Tau Protein Burden in Alzheimer’s Transgenic Mice , 2012, Current Alzheimer research.

[13]  M. Wenk,et al.  Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration , 2012, The Journal of Neuroscience.

[14]  K. Abel,et al.  Evaluation in vitro of synthetic curcumins as agents promoting monocytic gene expression related to β-amyloid clearance. , 2012, Chemical research in toxicology.

[15]  K. Abel,et al.  Curcumins Promote Monocytic Gene Expression Related to β-Amyloid and Superoxide Dismutase Clearance , 2011, Neurodegenerative Diseases.

[16]  M. Soni,et al.  Safety assessment of a solid lipid curcumin particle preparation: acute and subchronic toxicity studies. , 2011, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[17]  Sahdeo Prasad,et al.  Turmeric, the golden spice: From traditional medicine to modern medicine , 2011 .

[18]  R. Tanzi,et al.  Curcumin Decreases Amyloid-β Peptide Levels by Attenuating the Maturation of Amyloid-β Precursor Protein* , 2010, The Journal of Biological Chemistry.

[19]  M. Lai,et al.  Cdk5-Mediated Phosphorylation of δ-Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity , 2010, The Journal of Neuroscience.

[20]  D. Baker,et al.  Inflammation in neurodegenerative diseases , 2010, Immunology.

[21]  G. Maru,et al.  Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. , 2010, Journal of agricultural and food chemistry.

[22]  M. Tansey,et al.  Molecular Neurodegeneration BioMed Central Review , 2009 .

[23]  K. Abel,et al.  Immune defects in Alzheimer's disease: new medications development , 2008, BMC Neuroscience.

[24]  Takashi Morihara,et al.  Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer's Disease , 2008, Journal of Pharmacology and Experimental Therapeutics.

[25]  Anna Kremer,et al.  Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration. , 2008, The American journal of pathology.

[26]  Robert A Newman,et al.  Bioavailability of curcumin: problems and promises. , 2007, Molecular pharmaceutics.

[27]  B. Hyman,et al.  Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model , 2007, Journal of neurochemistry.

[28]  L. Tsai,et al.  p25/Cyclin-Dependent Kinase 5 Induces Production and Intraneuronal Accumulation of Amyloid β In Vivo , 2006, The Journal of Neuroscience.

[29]  M. Ohno,et al.  Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation , 2006, The Journal of Neuroscience.

[30]  L. Lannfelt,et al.  The Arctic Alzheimer mutation facilitates early intraneuronal Aβ aggregation and senile plaque formation in transgenic mice , 2006, Neurobiology of Aging.

[31]  J. Koenigsknecht-Talboo,et al.  Microglial Phagocytosis Induced by Fibrillar β-Amyloid and IgGs Are Differentially Regulated by Proinflammatory Cytokines , 2005, The Journal of Neuroscience.

[32]  J. D. McGaugh,et al.  Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice , 2005, Neuron.

[33]  Fusheng Yang,et al.  Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo* , 2005, Journal of Biological Chemistry.

[34]  Li-Huei Tsai,et al.  Cdk5 deregulation in the pathogenesis of Alzheimer's disease. , 2004, Trends in molecular medicine.

[35]  H. Pant,et al.  Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. , 2004, Biochimica et Biophysica Acta.

[36]  E. Park,et al.  Curcumin Suppresses Janus Kinase-STAT Inflammatory Signaling through Activation of Src Homology 2 Domain-Containing Tyrosine Phosphatase 2 in Brain Microglia 1 , 2003, The Journal of Immunology.

[37]  David S. Park,et al.  Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Li-Huei Tsai,et al.  Aberrant Cdk5 Activation by p25 Triggers Pathological Events Leading to Neurodegeneration and Neurofibrillary Tangles , 2003, Neuron.

[39]  Minh Dang Nguyen,et al.  Cyclin-Dependent Kinase 5 in Amyotrophic Lateral Sclerosis , 2003, Neurosignals.

[40]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[41]  F. Shie,et al.  Early intraneuronal Aβ deposition in the hippocampus of APP transgenic mice , 2003 .

[42]  P. Seymour,et al.  Cdk5 as a drug target for the treatment of Alzheimer’s disease , 2002, Journal of Molecular Neuroscience.

[43]  A. Sun,et al.  Comparative Analysis of an Improved Thioflavin-S Stain, Gallyas Silver Stain, and Immunohistochemistry for Neurofibrillary Tangle Demonstration on the Same Sections , 2002, Journal of Histochemistry and Cytochemistry.

[44]  G. Cole,et al.  The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse , 2001, The Journal of Neuroscience.

[45]  G. M. Cole,et al.  Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology , 2001, Neurobiology of Aging.

[46]  Oliver Wirths,et al.  Intraneuronal Aβ accumulation precedes plaque formation in β-amyloid precursor protein and presenilin-1 double-transgenic mice , 2001, Neuroscience Letters.

[47]  L. Tsai,et al.  Cdk5 on the brain. , 2001, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[48]  K. Ishiguro,et al.  Calpain-dependent Proteolytic Cleavage of the p35 Cyclin-dependent Kinase 5 Activator to p25* , 2000, The Journal of Biological Chemistry.

[49]  L. Tsai,et al.  Neurotoxicity induces cleavage of p35 to p25 by calpain , 2000, Nature.

[50]  L. Tsai,et al.  Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration , 1999, Nature.

[51]  L. Tsai,et al.  The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity , 1998, Nature.

[52]  H. Ammon,et al.  Pharmacology of Curcuma longa , 1991, Planta medica.

[53]  J. Bremer,et al.  Metabolism of very long-chain monounsaturated fatty acids (22:1) and the adaptation to their presence in the diet. , 1982, Journal of lipid research.

[54]  L. Tsai,et al.  TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice. , 2017, Journal of Alzheimer's disease : JAD.

[55]  G. Lithgow,et al.  Curcumin and neurodegenerative diseases , 2013, BioFactors.

[56]  Han-Chang Huang,et al.  Curcumin-mediated neuroprotection against amyloid-β-induced mitochondrial dysfunction involves the inhibition of GSK-3β. , 2012, Journal of Alzheimer's disease : JAD.

[57]  Huidong Tang,et al.  PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes. , 2010, Journal of Alzheimer's disease : JAD.

[58]  Shrikant D. Mishra,et al.  The effect of curcumin (turmeric) on Alzheimer's disease: An overview , 2008, Annals of Indian Academy of Neurology.

[59]  V. Menon,et al.  Antioxidant and anti-inflammatory properties of curcumin. , 2007, Advances in experimental medicine and biology.

[60]  R. Leboeuf,et al.  Early intraneuronal Abeta deposition in the hippocampus of APP transgenic mice. , 2003, Neuroreport.

[61]  T. Bayer,et al.  Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. , 2001, Neuroscience letters.

[62]  L. Mucke,et al.  TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. , 2001, Nature medicine.

[63]  Z. Nagy,et al.  New temperature modification makes the Bielschowsky silver stain reproducible , 2000, Acta Neuropathologica.